Asthmatic patients respond to inhaled stimuli with an excessive reduction in airway caliber, a phenomenon known as airway hyperresponsiveness (AHR). AHR is highly complex and reflects multiple processes that manifest over a large range of length and time scales. At one extreme, molecular interactions determine the force generated by airway smooth muscle (ASM). At the other extreme, the spatially distributed constriction of the many branches of the airway tree lead to persistent difficulties in breathing. Similarly, conventional asthma therapies are pharmacological and operate at the molecular level, while clinical outcomes are evaluated in terms of global lung function. These extremes are linked by numerous events operating over intermediate scales of length and time. Thus, AHR is an emergent phenomenon that is extremely challenging to understand in its entirety. This in turn limits our understanding of asthma and confounds the interpretation of experimental studies that each can address physiological mechanisms over only a very limited range of scales. Our solution to this conundrum has been to construct a modular multi-scale mathematical model that links and integrates experimental data from multiple scales. The current manifestation of this model, which is the result of a multi-disciplinary collaboration between 5 investigators with complementary experimental and mathematical expertise, incorporates force production by actin-myosin dynamics, force regulation by Ca2+ dynamics, force-dependent tissue deformation, and airway constriction. While this model demonstrates feasibility for our project and, most importantly, establishes computational algorithms for modeling over a wide range of scales, it currently represents only an initial frame-work. Consequently, in this proposal, we intend to develop our unique multi-scale computational model of the lung to the point where it can be used to make realistic predictions of bronchoconstriction, thereby allowing us to identify those pathophysiologic mechanisms having the greatest impact on AHR. We will include in this extended model: 1) at the molecular level, the kinetics of the contractile proteins during regular cross-bridge cycling and during the latch-state and their contributions to force production, 2) at the cellular level, the Ca2+ signaling mechanisms that regulate ASM force production, 3) at the tissue level, the detailed balance of forces between contracting ASM and the opposing viscoelastic tissue that determine airway narrowing, and 4) at the organ level, the topographic distribution of ASM contraction dynamics that determine changes in mechanical impedance in the normal and hyperresponsive lung. By extensive iteration between theory and experimentation, the modules of the model will be individually validated to identify the key parameters that link between successive scales. The model will then be used to make testable predictions of molecular, cellular and tissue behavior. This will improve our understanding of the link between cellular pathophysiology and the clinical phenotype in asthma. PUBLIC HEALTH RELEVANCE: Many individuals worldwide suffer from asthma, an inflammatory lung disease characterized by excessive constriction of the airways. This excessive constriction, termed airway hyperresponsiveness (AHR) can be life- threatening and is the result of an extremely complicated sequence of events initiated at the molecular level by airborne allergens or other stimuli, and culminating at the organ level with difficulty in breathing. The objective of this research is to understand the sequence of events leading to AHR by using a mathematical model to integrate data from experimental studies that by themselves can only elucidate the details of each step. With this multi-scale approach, we will be able to identify key events in AHR that may serve as targets for therapeutic intervention.